Routes for the Synthesis of (2S)-2-Methyltetrahydropyran-4-one from Simple Optically Pure Building Blocks

Abstract

Routes to (2S)-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of (S)-5-hydroxyhex-1-en-3-one, derived either from an alkyl (S)-3-hydroxybutyrate or (S)-propylene oxide. Formation of the tetrahydropyran ring directly via an intramolecular oxy-Michael reaction under acid-catalysed conditions resulted in loss of optical purity, whereas proceeding through the intermediate (2S)-2-methyl-2,3-dihydropyran-4-one, via an oxidative Pd-catalysed ring closure, followed by hydrogenation of the alkenyl bond, preserved the optical purity. An alternative approach to (2S)-2-methyl-2,3-dihydropyran-4-one is also reported, again starting from an alkyl (S)-3-hydroxybutyrate by elaboration to a carbonyl-protected (6S)-6-methyl-5,6-dihydropyran-2,4-dione derivative, followed by partial reduction and dehydration. Alternatively, the carbonyl group can be reduced out completely in one step to furnish (2S)-2-methyltetrahydropyran-4-one directly after deprotection.

A Divergent Enantioselective Strategy for the Synthesis of Griseusins

“…Whereas the ester 11 was unstable under standard Sharpless dihydroxylation conditions (strong base), alternative use of NaHCO 3 led to intermediate 5 in excellent yield (84 %, 97 % ee ) 7. The corresponding synthesis of building block 6 was achieved in three steps from ethyl ( R )‐3‐hydroxybutyrate ( 12 )8 to set the stage for the key hydroxy‐directed CH olefination reaction.…”

Enantiomeric impurities in chiral catalysts, auxiliaries, and synthons used in enantioselective syntheses. Part 4

“…85 (3) Used as a building block in the synthesis of (2S)-2-methyltetrahydropyran-4-one. 86 (1) Used as a building block in the enantioselective Tsuji allytation. 91 (2) Used in the asymmetric epoxidation of alkenes mediated by chiral iminium slats.…”

Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses

“…Reissigs series of studies on lithiated alkoxyallenes led to the synthesis of a variety of useful heterocycles such as furans, pyrroles, pyridines, pyrimidines, and 1, 2-oxazines in a new efficient way. [7][8][9][10] Allenyl vinyl ketone with an alkoxyl substituent was highly reactive and ready underwent a Nazarov cyclization. [11,12] Deprotonation of 2,3-allenoates with lithium diisopropylamide (LDA) or tetrabutylammonium fluoride (TBAF) gave alkynylenolates, which could react with a variety of electrophiles, such as organohalides [13] and electron-withdrawing alkenes, [14] to afford highly functionalized a,a-disubstituted b-alkynyl esters in good to excellent yields under mild conditions, with a number of functional groups tolerated.…”